Project 1 seeks to apply a rational approach to the optimization of an effective CD8+ T cell response to HIV, capitalizing on viral fitness constraints to exploit the natural limits of HIV sequence evolution and CD8 immunodominance hierarchies and the plasticity of the immune response to block viral escape pathways. It also brings to bear recent advances in high throughput genomic sequencing to tackle the enormous sequence diversity of HIV, while applying novel and potent nanoparticle-based vaccine adjuvant systems. Most importantly, it serves to translate identified correlates of immune control of HIV into a novel humanized mouse model capable of recapitulating HIV infection as well as human HIV-specific immune responses. Thus, this work will enable for the first time the direct study of human (not rhesus monkey) immune responses against HIV (not SIV) in order to define the mechanisms of this protection and interatively improve vaccine approaches to optimize these effects. Project 1 responds to five specific objectives of the HIVRAD Program: 1) Identifying correlates of vaccineinduced immune protection to HIV/AIDS; 2) How vaccine design can better address the heterogeneity of HIV; 3) Improved animal model systems (and challenge viruses) to address vaccine efficacy; 4) Approaches to increase the immunogenicity of HIV antigens (e.g., novel adjuvants), and 5) Determining how immune cells can be mobilized to the portal of infection, and will address the following specific aims: Aim 1: Characterize the magnitude, kinetics, specificity and efficacy of HIV-specific CD8+ T cell responses in the humanized BLT mouse model to facilitate studies of HIV-specific vaccine immunity. Aim 2: Determine whether vaccination can overcome natural CD8+ T cell immunodominance hierarchies to avoid targeting of 'decoy' CD8 epitopes, and induce variant-specific CD8+ T cell responses. Aim 3: Determine whether the induction of strong, mucosal-homing CD8+ T cell responses by novel nanoparticle delivery systems can prevent the early systemic dissemination of HIV in BLT mice.